This invention was made with the assistance of the Government under a grant from the Public Health Service (ADAMHA Grant No. 5RO1DA 06251). The U.S. Government has certain rights in the invention.
The opium group of narcotic drugs are among the most powerfully acting and clinically useful drugs producing depression of the central nervous system. Drugs of this group are used principally as analgesics, but possess numerous other useful properties. Morphine, for example, is used to induce sleep in the presence of pain, check diarrhea, suppress cough, ease dyspnea, and facilitate anesthesia.
Unfortunately, morphine also depresses respiration; it increases the activity and tone of the smooth muscles of the gastrointestinal, biliary, and urinary tracts causing constipation, gallbladder spasm, and urinary retention; it causes nausea and vomiting in some individuals; and it may induce cutaneous pruritus. In addition to these actions, morphine and related compounds have other qualities which tend to limit their usefulness. Tolerance to the analgesic effect develops over a period of time so that the dose must be increased periodically to obtain equivalent pain relief. Tolerance and physical dependence develop, which combined with euphoria result in excessive use; leading to the risk of fatal overdosing, and addiction of those patients who have susceptible personalities.
The fact that the effects of endogenous opioids such as the enkephalins and exogenous opioids are mediated by at least three different types [mu (.mu.), delta (.delta.), kappa (.kappa.)] of opioid receptors raises the possibility that highly selective exogenous opioid agonist or antagonist ligands might have therapeutic applications. See W. R. Martin, Pharmacol. Rev., 35, 283 (1983). Thus, if a ligand acts at a single opioid receptor type or subtype, the potential side effects mediated through other opioid receptor types can potentially be minimized or eliminated.
The prototypical opioid antagonists, naloxone and naltrexone, are used primarily as pharmacologic research tools and for the reversal of toxic effects of opioids in case of overdose. Since these antagonists act at multiple opioid receptors, their application in other therapeutic areas or as pharmacologic tools appear to be limited.
Some progress has been made in the development of highly selective opioid antagonists. For example, Portoghese et al. (U.S. Pat. No. 4,816,586) disclose certain opiate analogs which possess high selectivity and potency at delta receptors. Minimal involvement was observed at mu and kappa opioid receptors. Pentapeptides structurally related to the enkephalins have also been reported to be highly delta-selective opioid antagonists. Such compounds (e.g., ICI 174864) currently are employed as pharmacologic probes of receptor function and structure, but they possess the disadvantage of low potency and poor penetration into the central nervous system (CNS). See J. W. Shaw et al., Life Sci., 31, 1259 (1982) and R. Cotton et al., Eur. J. Pharmacol., 97,331 (1984).
Thus, a continuing need exists for pharmacological approaches to the treatment of opioid dependence. More specifically, a need exists for an effective method to prevent morphine tolerance and/or dependence, using specific and potent opioid receptor antagonists, having a prolonged duration of action.